It is known that certain mevalonate derivatives inhibit the biosynthesis of cholesterol, cf. F. M. Singer et al, Proc. Soc. Exper. Biol. Med., 102, 370 (1959) and F. H. Hulcher,Arch. Biochem. Biophys., 146, 422 (1971). Nevertheless, the activity of these known compounds has not always been found to be satisfactory, i.e. to have practical application.
Recently, Endo et al, reported (U.S. Letters Pat. No. 4,049,495, U.S. Pat. No. 4,137,322 and U.S. Pat. No. 3,983,140) the production of fermentation products which were quite active in the inhibition of cholesterol biosynthesis. The most active member of this group of natural products, now called compactin, IIIa(R'.dbd.H) was reported by Brown et al [J. Chem. Soc. Perkin I 1165 (1976)] to have a complex mevalonolactone structure.
More recently, Monaghan et al in U.S. Pat. No. 4,231,938, which is incorporated herein by reference, reported an inhibitor, designated MK-803 and having the structure IIIa (R'.dbd.CH.sub.3) in Table I, which was isolated from an entirely different fermentation. Albers-Schonberg et al (U.S. Ser. No. 154,157, filed May 28, 1980) described a dihydro MK-803, designated III.sub.d (R'.dbd.CH.sub.3) in Table I, of equal potency to MK-803 isolated from the same fermentation as was MK-803. Patchett et al (U.S. Ser. No. 118,050, filed Feb. 4, 1980) describe dihydro and tetrahydro derivatives of MK-803 of different structures (III.sub.b,c and e (R'.dbd.CH.sub.3) in Table I), prepared by the catalytic hydrogenation of MK-803. Willard (U.S. Ser. No. 118,049, filed Feb. 4, 1980), described the preparation of the 8-hydroxy derivatives (IV.sub.a-e (R'.dbd.CH.sub.3) in Table I) which are the starting materials for the preparation of some of the novel compounds of this invention.
A tetrahydro analog III.sub.e (R'.dbd.H), of compactin was reported in published Japanese Application (Kokai) 55009-024.
Very recently a dihydro-analog of compactin of structure III.sub.d (R.dbd.H) was isolated from compactin fermentation broths as reported by Gullo et al, (U.S. Application Ser. No. 207,508, filed Nov. 17, 1980).
The preparation of the starting material, III.sub.d, (R'.dbd.CH.sub.3) as mentioned previously, is described by Albers-Schonberg et al in U.S. application Ser. No. 154,157, filed May 28, 1980, and is the product of the following fermentation with a strain of Aspergillus terreus, ATCC No. 20542, designated MF-4845 in the culture collection of MERCK & CO., Inc., Rahway, N.J.